Portal hypertension is a condition in which high blood pressure is present in the portal vein and its tributaries. It is often defined as a portal pressure gradient (the difference in pressure between the portal vein and the hepatic veins) of 5 mmHg or greater. Portal hypertension has profound clinical consequences, some of which can be associated with substantial morbidity and mortality. In most instances, an increase in intrahepatic resistance to blood flow is an early and critical component to portal hypertension. Recent evidence links perisinusoidal stellate cells (also known as Ito cells or lipocytes), which are analogous to tissue pericytes or vascular smooth muscle cells, to a role in portal hypertension via their capacity to regulate blood flow within the liver by contraction and constriction of sinusoids.
In an injured liver, hepatic stellate cells (HSCs) undergo a striking functional transition termed “activation”. Activation of HSCs in response to liver injury is a critical event in wound healing. For instance, HSC activation is a pivotal event in initiation and progression of hepatic fibrosis. HSC activation is characterized by cellular transdifferentiation from a vitamin A-storing quiescent adipocyte-like phenotype to a highly contractile and secretory myofibroblast phenotype. Dysregulation of transdifferentiation results in disruption of normal liver architecture, leading to negative pathophysiological consequences including portal hypertension, fibrosis and ultimately cirrhosis.
A critical feature of activation is the acquisition by HSCs of smooth muscle proteins, including smooth muscle alpha actin (αSMA) and myosin. As noted above, this transition is associated with an enhanced contractile phenotype; as a result of activation, HSC contractility is greatest in the injured liver. The increased contractility facilitates an increase in vascular resistance to the portal blood flow. Recent approaches to counterbalancing this increased portal vascular resistance due to the increased contractility of HSCs have focused on using vasodilating drugs (e.g., nitric oxide, organic nitrates, adrenolytics, calcium channel blockers, etc.). Such approaches, however, do not adequately treat, prevent, and/or ameliorate portal hypertension itself.
Accordingly there is a need for portal hypertension therapies designed to impede or halt further development of portal hypertension and/or reverse portal hypertension.